Welcome to the Gerland group -

Physics of Complex Biosystems

Vision

In physics, interactions between particles follow laws. In biology, interactions between biomolecules serve a function. These very different points of view are beginning to merge as research over the past years has demonstrated how, in some exemplary cases, the laws of physics constrain the implementation of biological function.

We investigate several such cases. For instance, we study how the spatial arrangement and coordination of enzymes determines the efficiency of a multi-step reaction. These spatial arrangements can be natural (as in biomolecular complexes) or engineered with the modern methods of bio-nanotechnology. In both cases, fundamental functional tradeoffs emerge, which must be characterized to understand the optimization of such systems.

Methods from theoretical physics help to describe the functioning of these complex biomolecular systems on a quantitative level, while the biological function leads to new questions, with many parallels in the engineering disciplines. Seen from this perspective, a bacterium is a microscopic bioreactor programmed by evolution to rebuild itself from a variable set of resources and in fluctuating environments. How is this bioreactor programmed? Which strategies enable the control of a diverse set of physico-chemical processes in a way as to robustly produce a highly complex product? Quantitative analysis and modeling facilitates insight into the underlying design principles.

 

 

Recent Research Highlights

A global resource allocation strategy governs growth transition kinetics of Escherichia coli

A grand challenge of systems biology is to predict the kinetic responses of living systems to perturbations starting from the underlying molecular interactions. Changes in the nutrient environment have long been used to study regulation and adaptation phenomena in microorganisms and they remain a topic of active investigation. Although much is known about the molecular interactions that govern the regulation of key metabolic processes in response to applied perturbations, they are insufficiently quantified for predictive bottom-up modelling. Here we develop a top-down approach, expanding the recently established coarse-grained proteome allocation models from steady-state growth into the kinetic regime. Using only qualitative knowledge of the underlying regulatory processes and imposing the condition of flux balance, we derive a quantitative model of bacterial growth transitions that is independent of inaccessible kinetic parameters. The resulting flux-controlled regulation model accurately predicts the time course of gene expression and biomass accumulation in response to carbon upshifts and downshifts (for example, diauxic shifts) without adjustable parameters. As predicted by the model and validated by quantitative proteomics, cells exhibit suboptimal recovery kinetics in response to nutrient shifts owing to a rigid strategy of protein synthesis allocation, which is not directed towards alleviating specific metabolic bottlenecks. Our approach does not rely on kinetic parameters, and therefore points to a theoretical framework for describing a broad range of such kinetic processes without detailed knowledge of the underlying biochemical reactions.

Quantifying the benefit of a proteome reserve in fluctuating environments

The overexpression of proteins is a major burden for fast-growing bacteria. Paradoxically, recent characterization of the proteome of Escherichia coli found many proteins expressed in excess of what appears to be optimal for exponential growth. Here, we quantitatively investigate the possibility that this overexpression constitutes a strategic reserve kept by starving cells to quickly meet demand upon sudden improvement in growth conditions. For cells exposed to repeated famine-and-feast cycles, we derive a simple relation between the duration of feast and the allocation of the ribosomal protein reserve to maximize the overall gain in biomass during the feast.

Optimal Compartmentalization Strategies for Metabolic Microcompartments

Intracellular compartmentalization of cooperating enzymes is a strategy that is frequently used by cells. Segregation of enzymes that catalyze sequential reactions can alleviate challenges such as toxic pathway intermediates, competing metabolic reactions, and slow reaction rates. Inspired by nature, synthetic biologists also seek to encapsulate engineered metabolic pathways within vesicles or proteinaceous shells to enhance the yield of industrially and pharmaceutically useful products. Although enzymatic compartments have been extensively studied experimentally, a quantitative understanding of the underlying design principles is still lacking. Here, we study theoretically how the size and enzymatic composition of compartments should be chosen so as to maximize the productivity of a model metabolic pathway. We find that maximizing productivity requires compartments larger than a certain critical size. The enzyme density within each compartment should be tuned according to a power-law scaling in the compartment size. We explain these observations using an analytically solvable, well-mixed approximation. We also investigate the qualitatively different compartmentalization strategies that emerge in parameter regimes where this approximation breaks down. Our results suggest that the different sizes and enzyme packings of α- and β-carboxysomes each constitute an optimal compartmentalization strategy given the properties of their respective protein shells.